Sepofarsen well tolerated, improves BCVA in Leber congenital amaurosis 10
Visual acuity rates and full-field light sensitivity improved after treatment with intravitreal sepofarsen in patients with Leber congenital amaurosis 10 due to the p.Cys998X mutation in the CEP290 gene.
“The most encouraging aspect of this trial was the surprising finding of mean improvements of visual acuity and full-field light sensitivity and, in some instances, unexpectedly outsized improvements even in subjects with baseline light perception vision,” Stephen R. Russell, MD, said at the virtual Association for Research in Vision and Ophthalmology meeting.
The 12-month multicenter phase 1b/2 trial included 11 subjects who received intravitreal injections of sepofarsen (ProQR Therapeutics), an RNA-based oligonucleotide, to treat Leber congenital amaurosis 10 (LCA10). Six participants received sepofarsen at a loading dose of 160 µg and a maintenance dose of 80 µg, and five participants received a loading dose of 320 µg and a maintenance dose of 160 µg; subjects received between one and four intravitreal injections in the eye with the worst best corrected visual acuity.
The primary outcomes were safety and tolerability, while secondary endpoints included improvements in best corrected visual acuity, full-field light sensitivity threshold and mobility. All subjects were seen at least once a month for up to 12 months.
The most common adverse event was the development of cataract in three of six subjects in the 160/80 µg cohort and in all five participants in the 320/160 µg cohort. In six cases, the cataracts progressed and interfered with visual acuity or assessments and were treated with cataract extraction and IOL placement. Visual acuity returned to pre-cataract treatment levels in all six cases, Russell said.
The mean visual acuity in treated eyes improved by 0.55 logMAR compared with an improvement of 0.12 logMAR in untreated eyes. The mean difference was statistically significant (P < .05), he said.
Red and blue light full-field light sensitivity threshold demonstrated improvement in light detection of almost 1 log unit, or nearly a 10-fold increase in sensitivity. For both measurements, the difference between the treated and untreated eye was statistically significant (P < .01).
Participants also underwent a mobility course tailored for the low level of visual acuity typical of LCA10, but the difference in treated and untreated eyes was not statistically significant, Russell said.
When comparing final BCVA improvement at 12 months between the two cohorts, Russell said the 320/160 µg dose did not show better visual outcomes when compared with the 160/80 µg dose.
“Before this trial, stabilization of vision was the expected outcome, but these clinical data demonstrate the potential for rapid and meaningful improvements in vision for subjects with LCA10,” he said.
Based on this data, recruitment has begun for a phase 2b/3 trial.
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Russell SR, et al. Results of a phase 1b/2 trial of intravitreal (IVT) sepofarsen (QR-110) antisense oligonucleotide in Leber congenital amaurosis 10 (LCA10) due to p.Cys998X mutation in the CEP290 gene. Presented at: Association for Research in Vision and Ophthalmology annual meeting; June 12, 2020 (virtual meeting).
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